This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A. Normal subjects and members of families with urea cycle disorders including hemizygous OTC deficient males (mild and severe), heterozygous OTC deficient females, affected patients with autosomal recessive urea cycle defects (citrullinemia, argininosuccinic aciduria, argininemia), their unaffected parents, and their sibs will be studied in the CRC to evaluate conversion of [15N-amide]glutamine to [15N]urea. This will be compared to total urea production measured with infusion of [18O][13C]urea. Selected subjects will be studied twice under identical conditions to determine the variability of the measurements. Metabolic conversion will be correlated with the genotype and phenotype. B. Subjects will be studied under conditions of increased and decreased nitrogen intake to assess the effects of protein load and the size of the labile nitrogen pool on the measurement of flux from glutamine to urea. Normal subjects will also be studied with and without administration of arginine and alternative pathway drugs. C. Urea cycle patients, both symptomatic and asymptomatic, will be evaluated by nitrogen flux and their index of urea cycle activity defined by proportion transfer of 15N from glutamine to urea ([15N]urea/[15N]glutamine)will be correlated with phenotypic severity. At-risk urea cycle patients defined by combinations of either 1) family history, 2) plasma ammonia and amino acids, 3) urine orotic aciduria, 4) enzymatic analysis, and/or 5) DNA mutation analysis will be studied to determine whether their 15N index correlates with these other measures of phenotypic severity. Finally, subjects with molecularly or biochemically defined mitochondrial disorders will be studied for their baseline rates of ureagenesis on a low protein diet to determine whether mitochondrial abnormalities affect ureagenesis.